1. Field of the Invention
The present invention relates to the prevention of anesthesia-induced tau pathology and cognitive impairment and, more particularly, to an intranasal administration of insulin that prevents abnormal hyperphosphorylation of tau and cognitive impairment.
2. Description of the Related Art
Tauopathies are a family of age-associated neurodegenerative diseases which are characterized histopathologically by the abnormal hyperphosphorylation and aggregation of tau in the brain, and clinically by cognitive impairment and/or motor dysfunction. Tauopathies include frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17), corticobasal degeneration, Pick disease, progressive supranuclear palsy, Guam Parkinsonism dementia complex, dementia pugilistica also known as chronic traumatic encephalopathy or traumatic brain injury, ceroid neuronal lipofuscinosis, Hallerworden Sptaz disease, Alzheimer's disease and adults with Down syndrome. The abnormal hyperphosphorylation of tau results in not only the loss of microtubule assembly promoting and stabilizing protein function, but also a gain of toxic function; the abnormally hyperphosphorylated tau sequesters normal tau as well as the other two microtubule associated proteins (MAPs), MAP1 and MAP2, and causes disruption of microtubules.
The majority of tauopathy cases have the sporadic form of the disease. It is well established that elderly individuals are at increased risk of cognitive decline after anesthesia or surgery. Though the long-term effect of anesthesia on cognition is still under debate, anesthesia may accelerate preexisting but asymptomatic neurodegenerative changes in the brain and thus promote the development of a tauopathy. Evidence from animal models suggests that anesthetic exposure can increase tau hyperphosphorylation, and cause significant learning and memory deficits in aged rodents.
Impaired brain insulin signaling pathways have been implicated in the development of Alzheimer's disease (AD), a common tauopathy. Decreases in the levels and activities of several components of the insulin signaling pathway have been found in AD brain. In agreement with the proposed role of insulin signaling in cognition, intranasal administration of insulin has been reported to improve memory in healthy humans and in individuals with mild cognitive impairment and AD. Animal studies also show improved general behavioral performance and cognition in normal and diabetic mice after treatment with intranasal insulin. It has also been reported that insulin can affect the stability, production, degradation and aggregation of Aβ, leading to reduced neurotoxicity. However, whether intranasal insulin treatment prevents or ameliorates anesthesia-induced tau hyperphosphorylation, which is crucial to neurodegeneration, has not been reported.
Transgenic mouse models that express AD-causing mutations, i.e., mutation in amyloid precursor protein and presenilin, produce only Aβ plaques and not tau pathology. Whereas transgenic mouse models that express tau mutations seen in FTDP-17 produce only tau pathology and not Aβ plaques. The 3xTg-AD mouse model is a dual model of AD and FTDP-17 in which mutations of two different diseases are expressed to produce both Aβ and tau pathologies. To date no tau mutations have been found in AD patients.